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Pancreatic Glucagonoma Metastasising to the Right Ovary Five Years After Initial Surgery: a Case Report

Pancreatic Glucagonoma Metastasising to the Right Ovary Five Years After Initial Surgery: a Case Report

JOP. J (Online) 2013 Sep 10; 14(5):510-514.

CASE REPORT

Pancreatic Glucagonoma Metastasising to the Right Five Years after Initial Surgery: A Case Report

David Graham Watt 1, Sanjay Pandanaboyana 4, Charles Simon Herrington 2, Iain S Tait 3

1General Surgery, 2Department of Pathology, and 3Hepatobiliary and Pancreatic Surgery, Ninewells Hospital and Medical School. Dundee, Scotland, United Kingdom. 4Hepatobiliary and Transplant Surgery, St James University Hospital. Leeds, West Yorkshire, United Kingdom

ABSTRACT Context Glucagonomas of the pancreas are neuroendocrine tumours (NETs) that arise from well-differentiated neuroendocrine cells within the pancreatic islets. They are considered to be aggressive NETs and often have metastases at initial presentation. In contrast localised glucagonoma without metastatic spread may have prolonged disease free survival with radical resectional surgery. Case report The authors present a case of a glucagonoma that initially presented with classical necrolytic migratory erythema and a large solitary mass in the body and tail of the pancreas that was surgically resected. Five years after surgery the patient presented with increased serum levels and a mass in the right ovary. Pathology of the resected ovary after oophorectomy identified this as an isolated metastatic glucagonoma. Conclusion Glucagonoma is a rare pancreatic NET that has significant malignant potential. This is the first case of a pancreatic glucagonoma metastasising to the ovary 5 years after radical distal pancreatosplenectomy.

INTRODUCTION [3] and has an incidence of 1 in 20,000,000 per year [4]. Pancreatic neuroendocrine tumours (NETs) are rare tumours of the pancreatic islet cells. NETs arise The authors present a case of pancreatic from mature endocrine cells in the pancreas or glucagonoma localised to the body and tail of the multi-potent stem cells and express chromogranin pancreas that was resected in 2007 by laparoscopic A, and/or neuron-specific enolase. distal pancreatosplenectomy. In February 2012 (5 NETs may also secrete neuropeptides that may years later) the patient presented with raised cause clinical symptoms or syndromes, such as glucagon levels and a mass in the pelvis on cross- Zollinger-Ellison syndrome () or sectional imaging. At laparoscopy a large solitary necrolytic migratory erythema (glucagonoma). right ovarian mass was identified and resected. Pathological examination of the ovary identified this There are various types of NETs including as metastatic NET consistent with glucagonoma. , , , This is the first reported case of isolated metastatic tumours and glucagonomas [1]. Surgery is the only glucagonoma in the ovary, five years after resection curative treatment for those tumours that are of a primary pancreatic glucagonoma. localised at presentation [2]. A glucagonoma is derived from the alpha cells of the pancreas. As the CASE REPORT name suggests, these cells are usually responsible A 62-year-old lady presented to the dermatology for the production of glucagon in the body. clinic with a 36-month history of dermatosis Glucagonoma was first described by Becker in 1942 affecting the lower legs, axillae, groins and sub- mammary regions (Figures 1 and 2). The rash was Received June 1 st , 2013 – Accepted August 2 nd , 2013 intermittent in nature, non-pruritic, associated with Key words Glucagonoma; Metastasis; Neuro- hair thinning, and had not responded to topical endocrine Tumors; Ovarian ; Pancreatic Neoplasms treatments. Skin patch testing was negative and Abbreviations NET: neuroendocrine tumour therefore skin biopsies were taken. These biopsies Correspondence Iain S Tait Department of General Surgery; Ninewells Hospital and showed necrolytic migratory erythema. Blood tests Medical School; Dundee DD1 9SY; Scotland; United Kingdom were ordered to include minerals and electrolytes, Phone: +44-1382.660.111; Fax: +44-1382.496.361 chromogranin A and glucagon levels. Zinc levels E-mail: [email protected] were found to be low, N-terminal glucagon raised at

JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 14 No. 5 – September 2013. [ISSN 1590-8577] 510 JOP. J Pancreas (Online) 2013 Sep 10; 14(5):510-514.

Figure 1. Dermatosis affecting the axilla that was shown to be Figure 2. Dermatosis affecting the lower legs that was shown to necrolytic migratory erythema following skin biopsy. be necrolytic migratory erythema following skin biopsy.

965 ng/L (reference range: 0-250 ng/L) and c- Five years after laparoscopic distal pancreato- terminal glucagon raised at 580 ng/L (reference splenectomy, surveillance glucagon levels showed a range: 0-150 ng/L). The biochemical diagnosis of a slight elevation whilst the patient remained pancreatic glucagonoma was confirmed and cross- otherwise well and asymptomatic. CT scanning sectional imaging demonstrated a 5 cm mass lesion showed a suspicious lesion in the distal small bowel, in the body and tail of the pancreas with no deep in the pelvis, with mucosal thickening and evidence of nodal disease or other metastatic hyper-enhancement. This was thought to be a spread (Figure 3). primary neuroendocrine tumour of the small bowel (Figure 4), as this would be regarded as an unusual The patient underwent a laparoscopic radical site for recurrence of a primary pancreatic NET. antegrade pancreatosplenectomy in February 2007 and the patient made an excellent post-operative recovery. Pathology confirmed this to be a neuroendocrine tumour with evidence of glucagon production, staged as pT2, pN0, pMx. Histology demonstrated a uniform appearance with islands and trabeculae of cells with pink cytoplasm and open nuclei. These features were in keeping with a glucagonoma that was completely excised (R0). A baseline early post-operative scan at 3 months showed no evidence of occult metastatic disease. Genetics showed no evidence of mutation in the MEN 1 gene and, following surgery the necrolytic migratory erythema rash rapidly resolved. The patient was placed on a surveillance programme of 6 monthly monitoring of serum glucagon levels and annual CT scan of chest and Figure 3. Cross sectional CT scanning showing a mass in the tail abdomen. of the pancreas (red arrow).

JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 14 No. 5 – September 2013. [ISSN 1590-8577] 511 JOP. J Pancreas (Online) 2013 Sep 10; 14(5):510-514.

the right ovary looked markedly abnormal and contained a large tumour, with no evidence of peritoneal disease, and no evidence of metastases. A laparoscopic right oophorectomy was performed and the patient made a good post- operative recovery and was discharged home. Macroscopically, the ovary was enlarged, measuring 50x40x55 mm, and weighed 55 g. It had a nodular appearance with an intact outer capsule. On sectioning, the ovary contained a multilocular cystic lesion, the largest cystic space measuring 20 mm in diameter. The non-cystic areas of the ovary had a yellow cut surface. Microscopic analysis Figure 4. Cross sectional CT scanning demonstrating an demonstrated tumour cells with monomorphic abnormality in the pelvis, thought to be dilated terminal ileum with mucosal thickening and hyper-enhancement (red arrow). nuclei and pale pink cytoplasm arranged predominantly in glandular and trabecular structures (Figure 5ab). Immunohistochemistry As there was uncertainty of the nature of the mass showed diffuse expression by tumour cells of lesion in the distal small bowel, which was cytokeratin 18 and synaptophysin (Figure 5c), with considered to be a most unusual site for focal expression of chromogranin and cytokeratin glucagonoma recurrence, a laparoscopy was 19, and cytoplasmic positivity for glucagon (Figure performed. At laparoscopy, the entire small bowel 5d). Overall the appearances indicated a was examined and no lesion identified. However, neuroendocrine tumour, and were compatible with

Figure 5. Photo microscopy from the resected ovarian specimen. a. This panel shows a low power view stained with haematoxylin and eosin (H&E; total magnification x40). The tumour is shown with the black arrow and ovarian cortex with yellow arrow. b. This panel is a high power view of the tumour cells, confirming the neuroendocrine appearance (H&E; total magnification x200). c. Section stained with synaptophysin which is a marker of neuroendocrine differentiation (total magnification x200). d. Section of tumour stained with glucagon, in keeping with metastatic glucagonoma (total magnification x200).

JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 14 No. 5 – September 2013. [ISSN 1590-8577] 512 JOP. J Pancreas (Online) 2013 Sep 10; 14(5):510-514. an ovarian metastasis from the original [11]. Our case further demonstrates that glucagonoma. The patient remains well at 16 laparoscopic surgery is safe and effective for months follow-up after oophorectomy, and with no treating neuroendocrine tumours of the pancreas, evidence of any further metastatic disease (now and curative resection can be achieved with good more than 6 years after laparoscopic resection of post-operative outcomes. the primary glucagonoma). Pancreatic NETs usually spread to the liver, DISCUSSION and peritoneum [1, 2, 3, 4, 5], and there are currently no reported cases of primary The first pancreatic “-producing tumours” neuroendocrine tumours of the pancreas were described by Wilder et al. in 1927, when he metastasizing to the . The exact mechanism described a patient with a metastatic pancreatic of spread of intra-abdominal tumours to the ovaries tumour and hypoglycaemia [1]. Later, the Zollinger- is unclear. However, there are three potential Ellison syndrome and glucagonoma syndrome were theories that may explain this pattern of metastatic described [1]. Glucagonomas more commonly affect spread. Firstly, surface implantation of tumour women aged 40-60-year-old [4, 5]. They are remnants onto the ovary from the primary tumour typically slow growing and are located in the body site seems the most logical explanation. This is and tail of the pancreas in more than 50% of cases more common in situations where there is evidence [1, 4]. Patients often present with a typical para- of peritoneal carcinomatosis [12]. Some authors neoplastic syndrome (glucagonoma syndrome) have commented on the fact that metastases are characterised by a specific dermatitis (necrolytic more common in the right ovary than the left. This migratory erythema), intolerance, weight further gives weight to the idea that spread is by loss and anaemia [1, 3, 4]. Other associated surface implantation as detached tumour fragments symptoms may include gastrointestinal from the primary tumour will be directed towards disturbance, deep venous thrombosis and the right iliac fossa by the slope caused from the stomatitis. Often the biggest clue to the diagnosis is mesenteric attachments [12]. This same mesentery the distinctive rash of necrolytic migratory almost acts as a barrier or shield for the left ovary, erythema [6]. These clinical features are due to the providing some protection. Our patient developed a effects of excess glucagon (which causes increased right ovarian metastasis only. However, the absence glycogenolysis, gluconeogenesis, lipolysis and of widespread peritoneal disease and the fact that secretion [1]). Glucagon also inhibits the ovarian surface often remains intact have been pancreatic and gastric secretion and reduces gut cited as evidence against the surface implantation motility [1, 3]. theory [12]. The second hypothesis is that Patients with glucagonoma of the pancreas with no metastases occur via lymphatic spread. The third evidence of metastases at presentation have a hypothesis is that of haematological dissemination chance of cure with complete surgical resection of of metastatic disease, but haematological spread of the tumour. This is usually in the form of a radical pancreatic tumours to the ovaries is very rare. If it distal [2] for tumours in the body occurs these tumours will usually involve the liver and tail of the pancreas. Whipple’s pancreatico- and spread via the portal [13]. duodenectomy may be performed for tumours in CONCLUSION the head of the pancreas. Pancreatic glucagonoma is an extremely rare NET Radical antegrade pancreatosplenectomy may be that is most frequently located in the body and tail performed laparoscopically (as in this patient), with of the pancreas. Primary pancreatic glucagonoma recent studies reporting comparable oncological usually presents with symptoms related to a outcomes to open surgery [7, 8, 9]. and can be difficult to A recent review by Jusoh and Ammori [10] and a diagnose. Often the biggest clue to the diagnosis is a recent meta-analysis by Venkat et al. [11] analysed distinctive rash (necrolytic migratory erythema) 11 and 18 studies respectively, comparing that can affect the entire body. Pancreatic laparoscopic and open distal . glucagonomas frequently have liver metastases (50- They found that laparoscopic distal pancreatectomy 70%) at presentation and should be considered as is associated with lower blood loss and reduced aggressive NETs with malignant potential. This hospital stay. Laparoscopic distal pancreato- paper reports on the very unusual occurrence splenectomy also has a lower risk of post-operative where a large primary pancreatic glucagonoma complications and wound infections and does not metastasized to the right ovary five years after the have a significantly longer operating time [11]. initial curative surgery, and highlights the need for From an oncological point of view, margin positivity long-term surveillance of patients with pancreatic was also comparable with the laparoscopic NETs. technique when compared to the open technique

JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 14 No. 5 – September 2013. [ISSN 1590-8577] 513 JOP. J Pancreas (Online) 2013 Sep 10; 14(5):510-514.

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JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 14 No. 5 – September 2013. [ISSN 1590-8577] 514

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